Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30]>CN(C)C=O.O>[CH3:11][O:10][C:8]1[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([O:1][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:9]=1
Reactant: COc1cc(O)c(C=O)cc1-c1cccs1
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCCOc1cc(OC)c(-c2cccs2)cc1C=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Ex-29C: To a solution of 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde from Ex-29B (0.10 g, 0.43 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (0.18 g, 1.3 mmol) and the resulting yellow slurry was heated to 80° C. Once at 80° C., 1-bromo-2-(2-methoxyethoxy)ethane (0.24 g, 1.3 mmol) was added dropwise in three equal portions with stirring at 1 h intervals. After the last addition, the reaction was stirred for an additional 1 h at 80° C. and cooled to room temperature. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers was sequentially washed with a saturated ammonium chloride solution (1×15 mL), water (1×15 mL), and brine (1×15 mL), dried over sodium sulfate, and concentrated to a brown oil. Silica gel chromatography (ethyl acetate/hexanes, 4:1) afforded 0.13 g (87%) of 4-methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-benzaldehyde as a pale yellow oil. 1H-NMR (300 MHz, CDCl3) δ 10.38 (s, 1H), 8.12 (s, 1H), 7.44 (dd, 1H), 7.30 (dd, 1H), 7.07 (dd, 1H), 6.57 (s, 1H), 4.33 (t, 2H), 4.00 (s, 3H), 3.94 (t, 2H), 3.74 m, 2H), 3.59 (m, 2H), 3.40 (s, 3H). HRMS (EI) Calcd. for C17H20O5S: 336.1031. Found: 336.1027.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]2[CH:18]=[C:17]([CH:19](C)[CH2:20][CH:21]=O)[O:16][N:15]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[BH-](OC(C)=O)(OC(C)=O)O[C:39](C)=O.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:24]([N:31]1[CH2:36][CH2:35][N:34]([CH2:39][CH2:21][CH2:20][CH2:19][C:17]2[O:16][N:15]=[C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[CH:18]=2)[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(CC=O)c1cc(-c2cccc(Oc3ccccc3)c2)no1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(CN2CCN(CCCCc3cc(-c4cccc(Oc5ccccc5)c4)no3)CC2)cc1
Yield: 42.6 %

Procedure:
About 2 min after dissolving 3-[3-(3-phenoxyphenyl)isoxazol-5-yl]butanal (31 mg, 0.101 mmol) and 1-benzylpiperazine (17.6, 0.101 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (64.2 mg, 0.303 mmol), cold acetic acid (6.9, 0.121 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 17 hr and followed the same processes as in Example 1 to obtain 20.1 mg (42.6%) of the target compound.
Reaction SMILES: [CH2:1]([C:5]1(O)[CH2:30][N:9]2[C@H:10]([C:26](C)(C)C)[CH2:11][C:12]3[C:17]([CH:8]2[CH:7](CO[SiH3])[C:6]1=[O:34])=[C:16](OC)[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[C:13]=3OC)[CH2:2][CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH2:54]>C1COCC1>[CH2:1]([CH:5]1[CH2:30][N:9]2[C@H:10]([CH2:26][OH:54])[CH2:11][C:12]3[C:17]([CH:8]2[CH2:7][C:6]1=[O:34])=[CH:16][C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(O)CN2C(c3c(c(OC)c(OC)c(OC)c3OC)C[C@H]2C(C)(C)C)C(CO[SiH3])C1=O
Reactant: O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCC1CN2C(CC1=O)c1cc(OC)c(OC)cc1C[C@H]2CO
Reaction time: 2 h

Procedure:
To a solution of 0.40 g of (6S)-3-Butyl-3-hydroxy-6-tert-butyldimethoxy-siloxymethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one in 13 ml of THF at 0° C. was slowly added a solution of 1.78 ml of tetrabutylammonium fluoride (1M in THF). The reaction mixture was stirred for 2 hours keeping the temperature between 0-5° C. The reaction mixture was poured into ice cooled water (49 ml) and then extracted two times with 30 ml of ethyl acetate. The organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was then purified by chromatography (silica gel, hexane/ethyl acetate 0-70%) to give 0.30 g of (6S)-3-Butyl-6-hydroxymethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one, MS (ISP) 348.3 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[O:8][C@H:9]3[CH:19]([OH:20])[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH2:12][C@H:10]3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)(C)(C)C.C(O)(C)C>C(Cl)Cl>[C:1]1([C:7]2[O:8][C@H:9]3[C:19](=[O:20])[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH2:12][C@H:10]3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1c2ccccc2C[C@H]2N=C(c3ccccc3)O[C@@H]12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CC(C)(C)O
Solvent: CC(C)O
Product: O=C1c2ccccc2C[C@H]2N=C(c3ccccc3)O[C@@H]12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Under argon to a solution of (±)-(3aR,9aR)-3a, 4,9,9a-tetrahydro 2-phenyl-naphth-[2,3-d]oxazol-9-ol in methylene chloride (10 ml) was added Dess Martin periodinane (640 mg) and tert-butylalcohol (56 mg). After 5 hours stirring at room temperature, isopropanol was added and the reaction mixture was filtered on a silica gel column (elution with cyclohexane: ethyl acetate, 40:1). Evaporation of solvents gave the title compound as an oil (150 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([N:25]=[C:26]=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C=NCc1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)NCc4ccccc4)cc23)CC1
Yield: 39.6 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 11.32 mg (0.0852 mMol) benzyl isocyanate, 9.4 mg of the title compound were recovered.
Reaction SMILES: [H-].[Na+].[CH3:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:27])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:15][CH:14]=1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CS(C)=O.C1(C)C=CC=CC=1>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][CH:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[C:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[CH3:3])=[CH:14][CH:15]=1)=[O:27])[CH3:34]
Reactant: CCOC(=O)CBr
Reactant: C[C@@H]1CCCN1CCCOc1ccc(C(=O)Cc2ccccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CCOC(=O)CC(C(=O)c1ccc(OCCCN2CCC[C@H]2C)cc1)c1ccccn1
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
A mixture of sodium hydride (0.092 g, 3.8 mmoL) in 10 mL of DMSO was stirred under N2 as the product from step 3 (1.0 g, 3.8 mmol) in 5.0 mL of DMSO was added dropwise. After the reaction was stirred for 30 min, a solution of ethyl bromoacetate (0.64 g, 8.83 mmol) in 6.0 mL of toluene was added dropwise, and the reaction was stirred at rt for 1 h. The reaction was then quenched with NH4Cl solution and the solvent was evaporated. The residue was extracted with CH2Cl2 (3×20 mL), combined, washed with saturated NaHCO3, saturated NaCl then dried over Na2SO4. The crude product was purified by flash chromatography using 10% MeOH in CH2Cl2 to give the product (0.65 g, 52%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[F:32][C:29]([F:30])([F:31])[C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][N:18]2[CH2:17][CH2:16][N:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[CH2:20][CH2:19]2)=[CH:24][CH:25]=1
Reactant: FC(F)(F)c1ccc(CCN2CCN(c3ccc(OCc4ccccc4)cc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1ccc(N2CCN(CCc3ccc(C(F)(F)F)cc3)CC2)cc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
1-(4-Benzyloxyphenyl)-4-[2-(4-trifluoromethylphenyl)ethyl]piperazine (0.94 g) was dissolved in ethanol (19 ml) and THF (19 ml). 10% palladium on carbon (94 mg) was added to the mixture and stirred at 50 to 60° C. under a hydrogen atmosphere for 8 hours. After being cooled to room temperature, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to afford the title compound as a gray powder (0.72 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]([F:22])([F:21])[CH2:12]OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:12][C:11]([F:22])([F:21])[F:10]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(Cl)cc1Br
Temperature: 100 °C
Yield: 108 %

Procedure:
A mixture of 2-bromo-4-chloro-phenol (2.0 g, 9.6 mmol), trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (3.8 g, 16.4 mmol), potassium carbonate (8.0 g, 59 mmol), and N,N-dimethylformaldehyde (80 ml) was heated to 100° C. for 72 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was treated with water (150 ml) and extracted with ethyl acetate (160 ml). The organic extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:4) to give 2-bromo-4-chloro-1-(2,2,2-trifluoro-ethoxy)-benzene (3.0 g, 100% yield). 1H NMR (acetone-d6) δ 4.80 (q, 2H, J=8.4 Hz, CH2), 7.28 (d, 1H, J=8.9 Hz, Ar), 7.45 (dd, 1H, J=8.9 Hz, J=2.5 Hz, Ar), 7.69 (d, 1H, J—2.5 Hz, Ar).
Reaction SMILES: [OH-].[Na+].C(O)C.[CH2:6]([C:20]1[CH:21]=[C:22]([C:25]([O:27]C)=[O:26])[NH:23][CH:24]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>O>[CH2:6]([C:20]1[CH:21]=[C:22]([C:25]([OH:27])=[O:26])[NH:23][CH:24]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCc1c[nH]c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCc1c[nH]c(C(=O)O)c1
Yield: 89.6 %

Procedure:
A solution (1 ml) of 2N sodium hydroxide was added to an ethanol solution (5 ml) of 0.22 g (0.69 mmol) of methyl 4-tetradecylpyrrole-2-carboxylate prepared in Example 9 and heated under reflux for 13 hours. Water was added to the resulting mixture, and then washed with ether. After acidifying the aqueous layer with hydrochloric acid, the mixture was extracted with ether and dried over anhydrous magnesium sulfate. The removal of the solvent afforded 0.19 g (95% yield) of 4-tetradecylpyrrole-2-carboxylic acid, m.p. 148°-150 ° C.
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][CH2:6][C:7]#[CH:8])=[O:4].[CH3:9][N:10]([CH3:12])[CH3:11]>C(#N)C>[Br-:1].[CH3:9][N+:10]([CH3:12])([CH3:11])[CH2:2][C:3](=[O:4])[NH:5][CH2:6][C:7]#[CH:8]
Reactant: CN(C)C
Reactant: C#CCNC(=O)CBr
Solvent: CC#N
Product: C#CCNC(=O)C[N+](C)(C)C
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a solution of 2-bromo-N-(prop-2-yn-1-yl)acetamide (0.6 g, 3.4 mmol) in acetonitrile (5 mL) was added trimethylamine (30% in MeOH, 5 mL). The mixture was stirred at room temperature for 16 h and concentrated in vacuo. The resulting residue was triturated with ether, resulting in the title compound (780 mg, 97%); LCMS: m/z=155.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ 9.03 (t, J=5.3 Hz, 1H), 4.17 (s, 2H), 3.95 (dd, J=5.4, 2.6 Hz, 2H), 3.23 (s, 9H), 2.09 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10]C=[C:12]([C:14](OC)=[O:15])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18](NC(C)C)(C)C.C([Li])CCC.[CH3:30][C:31]([CH3:33])=[O:32]>>[CH3:30][C:31]1([CH3:18])[C:33]2[S:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:13][C:12]=2[C:14](=[O:15])[O:32]1
Reactant: CC(C)=O
Reactant: COC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)Nc1nc2c(s1)C(C)(C)OC2=O

Procedure:
Methyl 2-(tert-butoxycarbonylamino)thiazole-4-carboxylate (purchased from Combi-Blocks), diisopropylamine, butyllithium, and dry acetone (purchased from Acros) were processed as described in Example 3D to obtain the title compound. MS (ESI+) m/z 285 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][C:14]([F:17])([F:16])[F:15])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:13][C:14]([F:15])([F:16])[F:17])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: [H][H]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1OC(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(OC(F)(F)F)c(C(=O)O)c1
Yield: 29 %

Procedure:
A mixture of 5-nitro-2-trifluoromethoxybenzoic acid (6.43 g, 25.6 mmol) and 128 mg of 10% Pd/C in 10 mL of absolute ethanol was stirred in a hydrogen atmosphere overnight at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness. The residue was triturated with diethyl ether and the crystals were filtered off and dried to afford 1.644 g (29%) of 5-amino-2-trifluoromethoxybenzoic acid.
Reaction SMILES: CN(C)/C=[CH:4]/[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19].C1C[O:25]CC1>P([O-])([O-])([O-])=O>[N+:18]([C:6]1[CH:7]=[C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:10][C:5]=1[CH:4]=[O:25])([O-:20])=[O:19]
Reactant: CN(C)/C=C/c1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: O=P([O-])([O-])[O-]
Product: O=Cc1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]
Yield: 52 %

Procedure:
To a solution of crude (E)-N,N-dimethyl-2-(2-nitro-4-(perfluoroethyl)phenyl)ethenamine (12.2 g, 39.2 mmol) in THF (300 mL) and pH 7.2 phosphate buffer (300 mL) was added NaIO4 (29.3 g, 137.2 mmol). After 2.5 hours an aliquot (˜0.3 mL) was removed, filtered and dried. The proton NMR of this sample indicated that the reaction was complete. The solids were removed and the filter cake was washed with EtOAc. The filtrate was washed with brine (2×100 mL), dried and concentrated. The concentrate was purified via flash chromatography (100% hexane to 5% EtOAc) to provide 2-nitro-4-(perfluoroethyl)benzaldehyde (5.4 g, 52%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[N-:13]=[N+:14]=[N-:15].[Na+]>ClCCl>[N:13]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)CCCCCCCCBr
Agent: [Na+]
Solvent: ClCCl
Product: [N-]=[N+]=NCCCCCCCCC(=O)O
Temperature: 60 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
9-bromononanoic acid (4a) (1.062 gr, 4.48 mmol) was dissolved in 15 mL of dry dichloromethane. Sodium azide (914 mg, 14 mmol) was then added and the mixture was stirred at 60° C. for 6 hours. The solution was cooled and diluted with 50 mL of dichloromethane and then washed with 1 M HCl (5×50 mL), brine (2×50 mL) and dried over magnesium sulfate. The mixture was then filtered and concentrated in vacuo to yield 90% of product 5a as a white solid. 1H-NMR (200 MHz, CDCl3): 1.3-1.5 (m; 8H), 1.5-1.7 (m; 4H), 2.33 (t; J=7.4 Hz; 2H), 3.25 (t; J=6.86 Hz; 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12.[O:25]=[C:26]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:27][C:28](O)=[O:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:28](=[O:29])[CH2:27][C:26]([NH:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:25])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12
Reactant: O=C(O)CC(=O)Nc1ccccc1
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccccc4)cc3F)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.3 %

Procedure:
To a solution of the amine 9 (80 mg, 0.235 mmol), 3-oxo-3-(phenylamino)propanoic acid (1) (42 mg, 0.235 mmol) and BOP (114.6 mg, 0.259 mmol) in DMF (2.4 mL), DIPEA (0.164 mL, 0.941 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between EtOAc and water. Organic phase was collected, washed with H2O and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (EtOAc/MeOH 95:5) followed by crystallization (MeOH) to afford the title compound 5b (11 mg, 9% yield). 1H NMR (DMSO-d6) δ (ppm): 10.55 (s, 1H), 10.19 (s, 1H), 8.5 (d, J=5.4 Hz, 1H), 7.86 (m, 2H), 7.59 (m, 2H), 7.49 (t, J=8.8 Hz, 1H), 7.41 (m, 2H), 7.30 (m, 2H), 7.05 (m, 2H), 6.69 (d, J=5.4 Hz, 1H), 3.99 (s, 3H), 3.52 (s, 2H). MS (m/z): 502.2 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](O)=[O:8])=[CH:5][C:4]([CH3:10])=[N:3]1.C(N(CC)CC)C.C(OC(Cl)=O)C.[N-:24]=[N+:25]=[N-:26].[Na+]>CC(C)=O.O>[N:24]([C:7]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=1)=[O:8])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C(=O)O)n(C)n1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C(=O)N=[N+]=[N-])n(C)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 34.4 %

Procedure:
To a solution of 1,3-dimethylpyrazol-5-carboxylic acid (500 mg, 3.57 mmol) in a mixture of acetone (10 mL) and water (5 mL) was added triethylamine (0.75 mL, 7.13 mmol). The mixture was cooled to 0° C. in a ice-bath. Ethylchloroformate (774 mg, 7.13 mmol) was then added and the resulting mixture was stirred for 1.5 hours at 0° C. To the mixture was added sodium azide (0.844 g, 13.0 mmol), and the mixture was stirred for another 1.5 hours. The mixture was concentrated, the residue was diluted with dichloromethane and washed with water. The organic layer was dried over MgSO4 and concentrated to give desired product (203 mg, 34%). 1HNMR (CDCl3) (δ) 6.60 (s, 1H), 4.11 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[C:33]1([CH2:39][CH2:40][NH2:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:41][CH2:40][CH2:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31]
Reactant: COc1ccc(CC2NCCc3c2cc(OC)c(OC)c3OC)cc1OC
Reactant: O=C(Br)CBr
Reactant: NCCc1ccccc1
Product: COc1ccc(CC2c3cc(OC)c(OC)c(OC)c3CCN2CC(=O)NCCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-phenyl-ethylamine
Reaction SMILES: [CH:1](Br)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C@H:16]1[CH2:21][NH:20][CH2:19][C@@H:18]([CH3:22])[NH:17]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]([N:20]1[CH2:19][C@H:18]([CH3:22])[NH:17][C@H:16]([CH3:15])[CH2:21]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CN(C(c2ccccc2)c2ccccc2)C[C@H](C)N1
Reaction time: 8 h

Procedure:
Benzhydryl bromide (4.33 g, 17.5 mmol) is added to s stirred solution of 2,6-cis-dimethylpiperazine (2.00 g, 17.5 mmol) and diisopropylethylamine (2.94 g, 22.8 mmol) in anhydrous dichloromethane (50 mL) at 0° C. The resultant mixture is allowed to stir overnight. After concentration and subsequent chromatography on silica gel, eluting with 2 M NH3/CH3OH in dichloromethane: 1-3%, benzhydryl-3,5-cis-dimethyl-piperazine is obtained as a white solid (3.0 g, 61% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[N:18]1([CH2:24][CH2:25][NH2:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CCO.Cl>[CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:26][CH2:25][CH2:24][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: NCCN1CCCCC1
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(NCCN2CCCCC2)c([N+](=O)[O-])c1
Temperature: 85 °C
Yield: 58 %

Procedure:
Following general procedure 2B: A mixture of N,N-diethyl-4-fluoro-3-nitrobenzamide (1.0 g, 4.2 mmol), 2-(1-piperidinyl)ethanamine (0.564 mL, 3.96 mmol) in 80% aq. EtOH (30 mL) was heated at 85° C. for 10 hours. After the usual work-up, the crude mixture was dissolved in 1 N HCl (40 mL) and washed with CH2Cl2 (2×10 mL). The aqueous layer was basified with 5 N NaOH (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to provide the title compound (0.800 g, 57%) as a bright yellow solid which was used without further purification. 1H-NMR (CDCl3): δ 8.64 (br s, 1H), 8.25 (d, J=2.4 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H), 3.41 (br s, 4H), 3.35 (br s, 2H), 2.64 (br s, 2H), 2.53 (br s, 4H), 1.61 (br s, 4H), 1.44 (br s, 2H), 1.19 (t, J=7.0 Hz, 6H).
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:8]=2[CH:7]=[CH:6][C:5]=1[O:17][CH2:18][CH2:19][CH2:20]Br)[CH2:2][CH3:3].BrCCC[N:26]1[CH2:30][C:29](=O)[N:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:27]1=[O:38].C([O-])([O-])=[O:40].[Cs+].[Cs+]>>[N:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[N:28]1[CH2:29][C:30](=[O:40])[N:26]([CH2:20][CH2:19][CH2:18][O:17][C:5]2[CH:6]=[CH:7][C:8]3[C:9]([C:13]([F:16])([F:15])[F:14])=[N:10][O:11][C:12]=3[C:4]=2[CH2:1][CH2:2][CH3:3])[C:27]1=[O:38]
Reactant: O=C([O-])[O-]
Reactant: O=C1CN(CCCBr)C(=O)N1c1ccccn1
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Agent: [Cs+]
Product: CCCc1c(OCCCN2C(=O)CN(c3ccccn3)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
A mixture of 7-propyl-3-trifluoromethyl-6-hydroxy-1,2-benzisoxazole from Example 7 (417 mg), 1-(3-bromopropyl)-3-(2-pyridyl)-imidazolidinedione (672 mg), and Cs2CO3 (867 mg) in DWF was allowed to react for 24 hours at RT. The mixture was filtered, then separated by preparative HPLC to yield the title compound as a white solid.